There were 46,420 estimated new cases and 39,590 deaths from pancreatic cancer in the United States in 2014. The incidence of carcinoma of the pancreas has markedly increased over the past several decades and ranks as the fourth leading cause of cancer death in the United States. (National Institutes of Health website). Despite the high mortality rate associated with pancreatic cancer, its etiology is poorly understood. Pancreatic cancer symptoms depend on the site of the tumor within the pancreas and the degree of tumor involvement.
The primary factors that influence prognosis are whether the tumor is localized and can be completely resected and whether the tumor has spread to lymph nodes or elsewhere. Exocrine pancreatic cancer is rarely curable and has an overall survival (OS) rate of less than 6%. The highest cure rate occurs if the tumor is truly localized to the pancreas; however, this stage of disease accounts for less than 20% of cases. For patients with localized disease and small cancers (<2 cm) with no lymph node metastases and no extension beyond the capsule of the pancreas, complete surgical resection is associated with an actuarial 5-year survival rate of 18% to 24%.
Surgical resection is the mainstay of curative treatment and provides a survival benefit in patients with small, localized pancreatic tumors. Patients with unresectable, metastatic, or recurrent disease are unlikely to benefit from surgical resection. Pancreatic tumors are resistant to treatment with chemotherapy and radiation. Surgical resection remains the primary modality when feasible; on occasion, resection can lead to long-term survival and provides effective palliation. The role of postoperative therapy (chemotherapy with or without chemoradiation therapy) in the management of pancreatic cancer remains controversial because much of the randomized clinical trial data available are statistically underpowered and provide conflicting results. (NIH website). Complete resection can yield 5-year survival rates of 18% to 24%, but ultimate control remains poor because of the high incidence of both local and distant tumor recurrence. Several phase III trials examined the potential overall survival (OS) benefit of postoperative adjuvant 5-FU-based chemoradiation therapy:
The Gastrointestinal Study Group (GITSG), a small randomized trial conducted by the GITSG in 1985 compared surgery alone with surgery followed by chemoradiation, reported a significant but modest improvement in median-term and long-term survival over resection alone with postoperative bolus 5-FU and regional split-course radiation given at a dose of 40 Gy. Charitè Onkologie (CONKO)-001, a multicenter phase III trial of 368 patients with resected pancreatic cancer who were randomly assigned to receive six cycles of adjuvant gemcitabine, showed gemcitabine compared with observation alone yielded improved survival rates at 5 years of 20.7% for the gemcitabine arm versus 10.4% for the observation-alone arm and at 10 years the survival rates were 12.2% for the gemcitabine arm versus 7.7% for the observation-alone arm. The ESPAC-3 (NCT00058201) trial randomly assigned 1,088 patients who had undergone complete macroscopic resection to either 6 months of 5-FU (425 mg/m2) and leucovorin (20 mg/m2) on days 1 to 5 every 28 days or 6 months of gemcitabine (1,000 mg/m2) on days 1, 8, and 15 every 28 days. Median OS was 23.0 months (95% CI, 21.1-25.0) for patients treated with 5-FU plus leucovorin and 23.6 months (95% CI, 21.4-26.4) for those treated with gemcitabine (HR=0.94; 95% CI, 0.81-1.08; P=0.39).
The National Institutes of Health has stated that additional trials are still warranted to determine more effective adjuvant therapy for this disease.
Treatment options under clinical evaluation include the following:
Gemcitabine and capecitabine (ESPAC-4).
Gemcitabine and erlotinib (CONKO-005).
Gemcitabine and erlotinib with or without 5-FU/capecitabine-based chemoradiation (RTOG-0848).
Platinum analog or fluoropyrimidine versus single-agent gemcitabine: Many phase III studies have evaluated a combination regimen with either a platinum analog (cisplatin or oxaliplatin) or fluoropyrimidine versus single-agent gemcitabine.
Not one of these phase III trials has demonstrated a statistically significant advantage favoring the use of combination chemotherapy in the first-line treatment of metastatic pancreatic cancer.
In summary, pancreatic cancer often has a poor prognosis, even when diagnosed early. Pancreatic cancer typically spreads rapidly and is seldom detected in its early stages, which is a major reason why it is a leading cause of cancer death. Signs and symptoms may not appear until pancreatic cancer is quite advanced and complete surgical removal isn't possible. Chemotherapy alone or in combination with surgery and/or radiation is does not alter long term prognosis.
It is therefore an object of the present invention to provide a new class of compounds for treatment of pancreatic cancer and other glutamine addicted cancers.
It is another object of the present invention to provide new compositions for treatment of pancreatic cancer and other glutamine addicted cancers.
It is a further object of the present invention to provide new delivery formulations demonstrating efficacy in treatment of pancreatic cancer using compounds not effective when administered by standard techniques.